HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features

Chiao-Ling Li; Chia-Lang Hsu; You-Yu Lin; Ming-Chih Ho; Ray-Heng Hu; Chi-Ling Chen; Tung-Ching Ho; Yung-Feng Lin; Shih-Feng Tsai; Sheng-Tai Tzeng; Chin-Fang Huang; Ya-Chun Wang; Shiou-Hwei Yeh; Pei-Jer Chen

doi:10.1159/000530699

HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features

Liver Cancer. 2023 Apr 17;13(1):41-55. doi: 10.1159/000530699. eCollection 2024 Feb.

Authors

Chiao-Ling Li¹, Chia-Lang Hsu^{2

3

4}, You-Yu Lin^{5

6}, Ming-Chih Ho⁷, Ray-Heng Hu⁷, Chi-Ling Chen⁵, Tung-Ching Ho¹, Yung-Feng Lin^{8

9}, Shih-Feng Tsai^{8

9}, Sheng-Tai Tzeng¹⁰, Chin-Fang Huang¹⁰, Ya-Chun Wang¹⁰, Shiou-Hwei Yeh^{1

11

12}, Pei-Jer Chen^{5

12

13}

Affiliations

¹ Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
² Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
³ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
⁵ Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
⁶ Genome and Systems Biology Degree Program, National Taiwan University College of Life Science, Taipei, Taiwan.
⁷ Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
⁸ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁹ Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
¹⁰ TCM Biotech International Corp., Taipei, Taiwan.
¹¹ Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
¹² Center of Precision Medicine, National Taiwan University, Taipei, Taiwan.
¹³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Abstract

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform.

Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC.

Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort.

Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.

Keywords: Classification; Liver cancer; TERT; Virus DNA integration.

Grants and funding

This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 111-2326-B-002-016-, 111-2634-F-002-017-, and 111-2326-B-002-017-), and the “Center of Precision Medicine” from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (NTU-CC-112L901401) and Academia Sinica, Taiwan (AS-KPQ-110-NGT and AS-KPQ-111-KNT-18-1).